Risk Factors Associated with Misuse of Soft Mist Inhaler in Patients with Chronic Obstructive Pulmonary Disease

Abstract

Purpose

The use of inhaled bronchodilators is the mainstay of treatment for patients with chronic obstructive pulmonary disease (COPD). Although the soft mist inhaler (SMI) was developed to overcome the disadvantages of pressurized metered dose and drug powder inhalers, misuse during handling has been frequently observed in many studies. However, few studies have focused on SMI misuse among patients with COPD. Thus, we aimed to assess and identify the risk factors associated with SMI misuse among patients with COPD.

Patient and Methods

In this prospective, observational, cross-sectional study, we enrolled patients with COPD who were undergoing SMI treatment between January 2018 and March 2020. An advanced nurse practitioner assessed the participants’ handling of the device by using a check list.

Results

Among 159 participants, 136 (85.5%) reported inhaler misuse. Duration of COPD and COPD assessment test (CAT) scores were positively associated with inhaler misuse; adherence and education level were negatively associated with inhaler misuse. In the multivariable analysis, a low educational level (less than high school), high CAT score (≥ 10), and short duration of COPD (≤ 2 years) were identified as risk factors for SMI misuse.

Conclusion

SMI misuse remains common among patients with COPD. Therefore, clinicians should pay close attention to their patients using SMIs, especially in the early period after the diagnosis of COPD.

Keywords:

• chronic obstructive pulmonary disease
• bronchodilators
• misuse
• soft mist inhaler

Introduction

Chronic obstructive pulmonary disease (COPD) is a common, progressive disease with persistent respiratory symptoms and airflow limitation.¹ COPD is a major cause of chronic morbidity and mortality and is the third leading cause of death in 2019.² Inhaler therapy is the mainstay treatment for patients with COPD; it delivers long-acting bronchodilators to the respiratory tract. Inhaled bronchodilators improve dyspnea, quality of life, and lung function and reduce acute exacerbation in patients with COPD.¹

The most common inhalational devices are the pressurized metered-dose inhaler (pMDI) and the drug powder inhalers (DPI). pMDI require precise coordination between inhalation and hand actuation for effective drug delivery; DPI require strong inhalation power to aerosolize the drug powder. The soft mist inhaler (SMI) is a propellant-free, multi-dose inhaler that does not require no the strong inhalation power. SMI provide slow-moving and long-lasting aerosolization, minimizing error in coordination between hand actuation and inhalation.³

For effective delivery, correct use of inhaler is essential. Errors in inhaler use are associated with acute exacerbation of COPD^4,5 reduced disease control,⁶ and increased economic burden.⁷ Previous studies have reported that misuse of pMDI and DPI is common in clinical practice.^5,8,9 Although many studies have investigated the error rates and factors associated with misuse, there are still some limitations; 1) they included participants using different devices (including SMI); 2) they included both COPD and asthma patients,^6,7,9–11 therefore have not focused on SMI misuse in patients with COPD. As a result, the risk factors associated with SMI misuse in patients with COPD are not well established. Although one study investigated SMI misuse in patients with COPD, it included a small number of participants,¹² thereby the risk factors associated with SMI misuse remain unclear.

Therefore, the aim of this study was to evaluate the error rate and identify risk factors associated with SMI misuse in patients with COPD who were using only SMI.

Materials and Methods

Study Design and Participants

This prospective, cross-sectional, and observational study included patients who were recruited from a tertiary hospital in South Korea. The patients were enrolled between January 2018 and March 2020. Inclusion criteria were as follows: 1) patients who were aged > 40 years with a diagnosis of COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria;¹³ 2) patients receiving ongoing SMI (Respimat^®) treatment for > 1 month. Exclusion criteria were as follows: 1) patients who were unable to communicate in written or spoken Korean; 2) patients who were unable to use SMI by themselves; 3) patients who were using an additional inhaler other than SMI. Exclusion criteria were assessed through direct communication with the consultant clinicians. This study included a portion of the previously published study inhaler cohort patient population.¹⁴

This study was conducted in accordance with the Declaration of Helsinki and was reviewed and approved by the Institutional Review Board of Yeungnam University Hospital (IRB number YUH IRB 2017–09-012). Written informed consent was obtained from all patients.

Measurements

Upon enrollment, information on patients’ age, sex, body mass index, duration of COPD, duration of SMI use, history of smoking, previous education and exacerbation history, level of education, and spirometry measurements were collected. The Modified Medical Research Council (mMRC) dyspnea and COPD Assessment Test (CAT) scores were also evaluated. The types of error as well as the critical errors considered in SMI are listed in Table 1. Critical errors included five steps and were defined as an error of actions affecting the deposition of inhaled particles in the lungs, thus resulting in little or no drug deposition.⁷ Adherence was self-reported and scored as good, partial, or poor based on whether the complete intake of daily dose, ie, if the daily dose intake (frequency or amount) exceeded or fell short of the requirement and whether the drug was taken just as needed or not at all.¹⁵ COPD exacerbation was defined as an acute worsening of respiratory symptoms necessitating additional therapy. Severe exacerbation was defined as the requirement for hospitalization or emergency room visits.¹⁶

Table 1 Error Rate of Participants for Each Step of Soft Mist Inhaler Use

Step for Soft Mist Inhaler use	Frequency of Errors
Keep cap closed, rotate device base half a turn until a “click” is heard.	28 (17.6)
Cap open until it clicks into open position	27 (17.0)
Hold the device in a correct position	0 (0.0)
Exhale before inhalation	113 (71.1)
Close lips around the mouthpiece end	13 (8.2)
Coordination between actuation and inhalation	43 (27.0)
Inhale deeply and slowly	46 (28.9)
Hold your breath for 5~10 seconds	66 (41.5)
Exhale slowly	25 (15.7)
Close cap	2 (1.3)
Patients performing at least one step incorrectly	136 (85.5)
Patients performing at least one critical step incorrectly	74 (46.5)

Notes: Data are presented as the number (%). Critical errors are shown in bold typeface.

Statistical Analysis

Continuous variables are expressed as the mean ± standard deviation and were compared using the Student’s t-test or Mann–Whitney U-test. Categorical variables were compared using the chi-squared test or Fisher’s exact test. A binary logistic regression analysis was used to access the risk factors associated with inhaler misuse. The included variables were sex, age (≤ 70 years, > 70 years), duration of COPD (≤ 2 years, > 2 years), duration of SMI use (≤ 2 years, > 2 years), CAT score (< 10, ≥ 10), and level of education (< high school, ≥ high school). Power analysis showed that the total sample size required to estimate the probability of inhaler misuse using the binary logistic regression analysis was 107 patients (95% power, α = 0.05, effect size = 0.15). Taking into account a drop-out rate of 20%, we set a target sample size of more than 130 patients.¹⁷

Results

Baseline Characteristics

The baseline characteristics are shown in Table 2. A total of 159 patients were enrolled in this study and their data were subsequently analyzed. The mean age of the patients was 70.39 ± 7.31 years; approximately 95% of the patients were male individuals (n=151). The mean duration of disease and SMI use was 3.33 ± 4.30 years and 2.59 ± 3.16 years, respectively. The patient cohort included approximately 89.3% current or ex-smokers. Of all patients, 22% experienced severe acute exacerbation in the previous year. Most patients had prior educational experience regarding inhaler use. Four-fifths of patients exhibited good adherence; approximately 40.3% had high school or higher education. The mean value of forced expiratory volume in 1 second was 61.56 ± 17.20; approximately 39% of the patients had mMRC ≥ 2 and CAT score ≥ 10.

Table 2 Clinical Characteristics of Study Participants

Characteristics	N = 159
Age (years)	70.39 ± 7.31
Male	151 (95.0)
BMI (kg/m^2)	23.33 ± 3.45
Duration of COPD (years)	3.33 ± 4.30
Duration of SMI use (years)	2.59 ± 3.16
Smoking status
Never smoker	17 (10.7)
Ex-smoker	117 (73.6)
Current smoker	25 (15.7)
Severe exacerbation in the prior year	35 (22.0)
Prior education in inhaler technique	151 (95.0)
Adherence
Good	126 (79.2)
Partial or poor	33 (20.8)
Education level
< High school	95 (59.7)
≥ High school	64 (40.3)
Spirometry
Percentage predicted FVC	74.69 ± 15.95
Percentage predicted FEV1	61.56 ± 17.20
FEV1/FVC (%)	57.80 ± 13.82
GOLD stage
1 (FEV1 > 80% predicted)	58 (36.5)
2 (50% ≤ FEV1 < 80% predicted)	79 (49.7)
3 (30% ≤ FEV1 < 50% predicted)	10 (6.3)
4 (FEV1 < 30% predicted)	12 (7.5)
mMRC score	1.31 ± 0.88
< 2	97 (61.0)
≥ 2	62 (39.0)
CAT score	10.08 ± 5.88
< 10	97 (61)
≥ 10	62 (39)

Notes: Data are presented as the mean ± standard deviation or number (percentage).

Abbreviations: BMI, body mass index; SMI, soft mist inhaler; COPD, chronic obstructive pulmonary disease; CAT, COPD assessment test; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; mMRC, modified Medical Research Council.

Assessment of Inhaler Technique

The error rate for each step of SMI is presented in Table 1. The 136 (85.5%) patients had at least one error in SMI use. The most frequently observed error was “no exhalation before inhalation” and “no breath-holding for 5–10 seconds”, observed in 71.1% and 41.5% of the patients, respectively. And 74 (46.5%) of the patients made at least one critical error. The most common critical errors were “failure to inhale deeply and slowly” and “poor coordination between hand actuation and inhalation”, observed in 39% and 27% of the patients, respectively.

Factors Associated with Any Error in SMI Usage

Factors associated with SMI misuse are listed in Tables 3 and 4. Among the various characteristics, duration of COPD ≤ 2 years, partial or poor adherence, < high school education level, and CAT score ≥ 10 were associated with inhaler usage errors (Table 3). Binary logistic regression analysis revealed that SMI misuse among patients with COPD were significantly associated with < high school education level (adjusted odds ratio (aOR) 3.258, 95% confidence interval (CI) 1.175–9.034; p=0.023), CAT score ≥ 10 (aOR 3.341, 95% CI 1.008–11.075; p=0.049, and duration of COPD ≤ 2 years (aOR 3.819, 95% CI 1.253–11.637 (Table 4).

Table 3 Characteristics of the Participants According to Any Error of SMI Use

Characteristics	Any Error of SMI Use		P value
	No (n=23)	Yes (n=136)
Age (years)	70.26 ± 7.09	70.41 ± 7.37	0.927
BMI (kg/m^2)	23.90 ± 2.93	23.25 ± 3.63	0.449
Duration of COPD (years)	2.70 ± 4.16	3.43 ± 4.32	0.451
≤ 2 years	18 (78.3)	76 (55.9)	0.043
> 2 years	5 (21.7)	60 (44.1)
Duration of SMI use (years)	2.44 ± 3.39	2.62 ± 3.14	0.810
≤ 2 years	19 (82.6)	84 (61.8)	0.053
> 2 years	5 (17.4)	52 (38.2)
Adherence			0.003
Good	23 (100)	103 (75.7)
Partial or poor	0 (0)	33 (28.2)
Education level			0.002
< High school	7 (30.4)	88 (64.7)
≥ High school	16 (69.6)	48 (35.3)
mMRC score	1.13 ± 0.87	1.35 ± 0.88	0.279
< 2	15 (65.2)	82 (60.3)	0.419
≥ 2	8 (34.8)	54 (39.7)
CAT score	7.96 ± 4.03	10.44 ± 6.07	0.016
< 10	19 (82.6)	78 (57.4)	0.022
≥ 10	4 (17.4)	58 (42.6)
GOLD stage			0.412
1 (FEV1 ≥ 80% predicted)	4 (17.4)	13 (9.6)
2 (50% ≤ FEV1 < 80% predicted)	12 (52.2)	85 (62.5)
3 (30% ≤ FEV1 < 50% predicted)	7 (30.4)	32 (23.5)
4 (FEV1 < 30% predicted)	0 (0)	6 (4.4)

Notes: Data are presented as the mean ± standard deviation or number (percentage).

Abbreviations: SMI, soft mist inhaler; BMI, body mass index; COPD, chronic obstructive pulmonary disease; mMRC, modified Medical Research Council; CAT, COPD assessment test; GOLD, global initiative for chronic obstructive lung disease; FEV₁, forced expiratory volume in 1 second.

Table 4 Risk Factors for Any Error of SMI Use by Binary Logistic Regression Analysis

Variable	Adjusted OR (95% CI)	P value
Education		0.023
≥ High school	Reference
< High school	3.258 (1.175–9.034)
CAT score		0.049
< 10	Reference
≥ 10	3.341 (1.008–11.075)
Duration of COPD		0.018
> 2 years	Reference
≤ 2 years	3.819 (1.253–11.637)

Notes: Data are presented as odds ratios and 95% confidence intervals. Model adjusted for age, sex, duration of COPD, duration of SMI use, CAT score, level of education, and inhaler adherence.

Abbreviations: SMI, soft mist inhaler; OR, odds ratio; CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease.

Discussion

Among the 159 patients with COPD using SMI, 85.5% exhibited at least one step of incorrect usage and 46.5% had at least one critical step of incorrect usage. The most frequently observed error was “exhale before inhalation”, and the most common critical error was “inhale deeply and slowly”. Low educational level, high respiratory symptoms (CAT score ≥ 10), and shorter duration of COPD were associated with SMI misuse.

Molimard et al reported inhaler device handling in real-life assessment of 2935 patients with COPD, including 625 SMI users. Among them, 46.9% exhibited at least one critical error, with dose delivery critical error (39.8%) being more common than dose preparation critical errors (12.5%). Furthermore, lack of synchronization between the hand and lung was the most common critical error (39.4%).⁵ Our study showed similar results, with 46.5% of patients exhibiting at least one critical error, and the coordination between actuation and inhalation (27.0%) was the second most common critical error.

Takaku et al reported inhaler device handling status in 216 patients with asthma and COPD, of which 46 used SMI.¹⁰ Even after initial instruction for using inhaler device, 70% of the patients made at least one error, of which device handling error (50%) was the most common one. No breath-hold (33%), no expiration before inspiration (30%), and incorrect inhaler positioning (24%) were other common errors observed in the study.¹⁴ In our study, a significant number of patients (approximately 17%) made dose preparation errors, described as an appropriate turning to open the cap.

Our study’s findings are consistent with those of previous research, demonstrating the association between a lower level of education and a higher rate of improper inhaler usage.^6,9,18 Zhang et al focused on inhaler technique using tiotropium bromide SMI and revealed that patients with lower education level (elementary, junior high, or high school) had a higher likelihood of misusing SMIs than that of patients with a higher educational level.¹² Respimat is an inhaler that requires precise instruction for usage, particularly while assembling the device. Patients should be assisted by physicians in confirming the accuracy of inhaler usage steps. Compared to individuals with lower educational levels, those with higher levels paid more attention to the educational program and were more willing and active in communicating with the trainers.

Higher CAT scores were associated with incorrect inhaler usage in previous studies. This could be explained by the fact that improved inhalation technique may allow more amounts of the inhalation drug to reach the lung. Zhang et al reported that better technique during the inhalation maneuver was accompanied by a lower CAT scores among patients with COPD using SMIs.¹² In a study conducted in Korea, CAT scores exhibited a negative correlation with acceptable inhaler use in older adult patients with respiratory disease.¹¹ However, a prospective, observational, cohort study conducted in Sweden, including 310 patients with COPD, revealed that critical errors were not associated with COPD symptoms, as assessed using CAT and mMRC scores.¹⁹ When viewed longitudinally, confusion factors, such as changes in patient’s symptoms and in inhaler, remain significant; thus, more research is required in this area. In groups using SMIs, our study offers supportive evidence regarding the association between disease control, as measured by CAT scores, and inhaler technique.

A notable finding in our study was that COPD duration ≤ 2 years was associated with inhaler misuse as assessed by multivariate analysis. Studies evaluating the relationship between disease duration and inhaler misuse are rare. One study reported that shorter disease duration was associated with inhaler misuse, but this study analyzed both COPD and asthma and did not adjust for other variables.²⁰ Another study investigated SMI misuse in patients with COPD and reported that the duration of COPD was associated with inhaler misuse (OR, 0.80), but this study included only 74 participants.¹² The strength of our study is that it focused on COPD patients, not asthmatics, and included a larger number of participants. With regard to our findings, after clinicians have diagnosed COPD and prescribed a new inhaler device, they should educate patients on proper inhaler technique and try to ensure that they use it correctly. However, our study was conducted in a single center, so this result could not be generalized to all patients with COPD. More research is needed on the relationship between the duration of COPD and inhaler misuse.

This study has several limitations. First, it was a single-center study of outpatients with COPD, and we excluded patients who were unable to communicate in written or spoken Korean; therefore, selection bias is unavoidable. Second, this study included a relatively small number of patients using SMI. However, the number of patients remained adequate in terms of the scope of the study, focusing only on those who used SMI. Third, comorbidities and other independent factors that may be linked to erroneous techniques were not assessed. However, our study is one of the few studies that have analyzed the status and risk factors associated with inhaler usage errors among patients with COPD using SMI. The fourth limitation of this study is the high proportion of male participants (95%). This is probably due to the fact that the prevalence of COPD in Korea is still higher in males than in females,²¹ this proportion was similar to another study performed from another center in Korea.¹¹ In addition, we included participants who were not sex-matched at enrolment, resulting in an extreme increase in the proportion of males. Finally, we have previously published an article reporting on inhaler device handling technique and risk factors for critical inhaler errors in Korean COPD patients. This study included some of the participants from the previous study, but there were some important differences: 1) while the previous study focused on the comparison of critical inhaler errors between different devices, this study focuses on SMI; 2) two studies had different inclusion criteria. The previous study allowed the enrollment of patients using multiple inhalers, whereas this study only included SMI users; 3) This study differs from the previous study by analyzing the error rates of each step of SMI usage and by analyzing the risk factors for any error in SMI use that is not a critical error.

Despite those limitations, this study evaluated SMI misuse and misuse related with factors in patients with COPD using only SMI.

Conclusion

In conclusion, inhaler misuse was common among COPD patients using only SMI. Low educational level, high respiratory symptoms, and a shorter duration of COPD were associated with SMI misuse. Therefore, physicians should be aware of the potential misuse of SMI in the course of COPD treatment, especially in the early period after the diagnosis of COPD.

Abbreviations

COPD, Chronic obstructive pulmonary disease; pMDI, pressurized metered-dose inhaler; DPI, drug powder inhaler; SMI, soft mist inhaler.

Ethics Statement

This study was conducted in accordance with all relevant tenets of the Declaration of Helsinki. The protocol was reviewed and approved by the Institutional Review Board of our hospital (no. Yeungnam University Hospital IRB 2017-09-012-001). Written informed consent was obtained from all patients.

Author Contributions

Concept and design: Jang JG, Lee YS, Hong KS, Ahn JH

Acquisition, analysis, or interpretation of data: Jang JG, Lee YS, Hong KS, Ahn JH

Drafting the manuscript: Jang JG, Ahn JH

Critical revision of the manuscript: Jang JG, Lee YS, Hong KS, Ahn JH

Statistical Analyses: Jang JG, Ahn JH.

Obtained Funding: Jang JG

All authors made substantial contributions to the study concept and design, acquisition or analysis and interpretation of the data, and drafting or critical revision of the article for important intellectual content. All authors agreed to submit the article to the current journal, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Acknowledgments

We sincerely thank Mi Suk Lee for assistance with this study and Mi Jeong Nam for her invaluable efforts with respect to the data collection.

Data Sharing Statement

The data that support the findings of this study are available on request from the corresponding author on reasonable request.

Additional information

Funding

This work was supported by the Yeungnam University Research Fund (2021).